The Transgenic Core provides all of our preclinical Projects (Projects 1-4) with state-of-the-art tools to enable manipulation of specific genes of interest in brain reward regions in the context of animal models of depression and antidepressant action. Centralizing these functions within a single Core derives substantial cost savings and ensures the proper and rigorous use of these approaches. First, numerous lines of transgenic and knockout mice, generated by Center investigators or obtained from other laboratories, are required for the Center's research. The Core is responsible for breeding, genotyping, and maintaining the progeny for use by the individual Projects, as well as providing the appropriate control mice. The Core is also be responsible for generating several new lines of transgenic and knockout mice required for the proposed program of research. Prominent among the existing and proposed new mouse lines are those that manipulate the expression of specific genes both temporally and spatially, i.e., inducible and cell-targeted mutations. Our group has substantial experiencewith these methods, which include the tetracycline gene regulation system and the Cre-loxP system. Indeed, Core research has succeeded in developing truly inducible, cell-targeted gene knockouts in brain reward regions. Second, the Core provides Project investigators with vectors for viral-mediated gene transfer, an important tool used in our research program. Center investigators have played a leading role nationally in these efforts, and now routinely use herpes simplex and adeno-associated viral vectors. This work includes viral expression of Cre to induce highly localized knockouts in brain, and the expression of small hairpin RNA's to induce knockdowns of genes via an RNA interference mechanism. We are very proud of the Core's achievements over the past 4 years, and we will work during the next Grant period to introduce further innovations in mouse mutagenesis and viral gene transfer for studies of depression.